Improving the efficacy of anticancer therapy remains an urgent and very important task. Screening of the individual genetic metabolism of cancer patients allows for prescribing adequate medication in the correct dose as well as for decreasing side effects associated with drug toxicity.
OBJECTIVE:
Estimation of a microarray-based method for genotyping of theUGT1A1, DPYD, GSTP1, and ABCB1 metabolic regulation genes to evaluate for an increased risk of toxicity of anticancer drugs.
METHODS:
The microarray was used to conduct genotyping of specimens taken from 115 cancer patients and 31 healthy donors.
RESULTS:
A microarray-based method for identification of the rs8175347, rs3918290, rs1695, and rs1045642 polymorphisms in the correspondingUGT1A1, DPYD, GSTP1, and ABCB1 genes has been developed for genotyping. The results obtained were in full concordance with those obtained using control sequencing. The frequencies of the rs8175347, rs3918290, rs1695, and rs1045642 genetic variations were 0.38, 0, 0.35, and 0.56, respectively.
CONCLUSION:
The implementation of this biochip-based method in diagnostic practice should increase the overall survival and quality of life of cancer patients, decrease the length of their hospital stay, and reduce treatment costs.
AmbudkarSV, Kimchi-SarfatyC, SaunaZE, GottesmanMM. P-glycoprotein: From genomics to mechanism. Oncogene. 2003; 22(47): 7468-85.
2.
BeutlerE, GelbartT, DeminaA. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: A balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA. 1998; 95(14): 8170-4.
3.
BosmaPJ, SeppenJ, GoldhoornB, BakkerC, Oude ElferinkRP, ChowdhuryJR, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem. 1994; 269(27): 17960-4.
4.
CarliniLE, MeropolNJ, BeverJ, AndriaML, HillT, GoldP, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005; 11(3): 1226-36.
5.
CerićT, ObralićN, Kapur-PojskićL, MacićD, BeslijaS, PasićA, et al. Investigation of IVS14 + 1G > A polymorphism of DPYD gene in a group of Bosnian patients treated with 5-Fluorouracil and capecitabine. Bosn J Basic Med Sci. 2010; 10(2): 133-9.
6.
CiccoliniJ, MercierC, EvrardA, DahanL, BoyerJC, DuffaudF, et al. A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy. Ther Drug Monit. 2006; 28(5): 678-85.
7.
DandaraC, SayiJ, MasimirembwaCM, MagimbaA, KaayaS, De SommersK, et al. Genetic polymorphism of cytochrome P450 1A1 (Cyp1A1) and glutathione transferases (M1, T1 and P1) among Africans. Clin Chem Lab Med. 2002; 40(9): 952-7.
8.
DeyS. Single nucleotide polymorphisms in human P-glycoprotein: its impact on drug delivery and disposition. Expert Opin Drug Deliv. 2006; 3(1): 23-35.
9.
EhmerU, LankischTO, ErichsenTJ, KalthoffS, FreibergN, WehmeierM, et al. Rapid allelic discrimination by TaqMan PCR for the detection of the Gilbert's syndrome marker UGT1A1*28. J Mol Diagn. 2008; 10(6): 549-52.
10.
FesenkoEE, HeydarovRN, StepanovaEV, AbramovME, ChudinovAV, ZasedatelevAS, et al. Microarray with LNA-probes for genotyping of polymorphic variants of Gilbert's syndrome gene UGT1A1(TA)n. Clin Chem Lab Med. 2013; 51(6): 1177-84.
11.
GeorgiadisP, DemopoulosNA, TopinkaJ, StephanouG, StoikidouM, BekyrouM, et al. Impact of phase I or phase II enzyme polymorphisms on lymphocyte DNA adducts in subjects exposed to urban air pollution and environmental tobacco smoke. Toxicol Lett. 2004; 149(1-3): 269-80.
12.
GsurA, HaidingerG, HintereggerS, BernhoferG, SchatzlG, MadersbacherS, et al. Polymorphisms of glutathione-S-transferase genes (GSTP1, GSTM1 and GSTT1) and prostate-cancer risk. Int J Cancer. 2001; 95(3): 152-5.
HallD, YbazetaG, Destro-BisolG, Petzl-ErlerML, Di RienzoA. Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. Pharmacogenetics. 1999; 9(5): 591-9.
15.
HarrawayJR, GeorgePM. Use of fully denaturing HPLC for UGT1A1 genotyping in Gilbert syndrome. Clin Chem. 2005; 51(11): 2183-5.
16.
HasegawaY, SarashinaT, AndoM, KitagawaC, MoriA, YoneyamaM, et al. Rapid detection of UGT1A1 gene polymorphisms by newly developed Invader assay. Clin Chem. 2004; 50(8): 1479-80.
17.
HayesJD, PulfordDJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995; 30(6): 445-600.
HoffPM. The tegafur-based dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines, UFT/leucovorin (ORZEL) and S-1: a review of their clinical development and therapeutic potential. Invest New Drugs. 2000; 18(4): 331-42.
20.
HuangCK, DulauA, Su-RickCJ, PanQ. Validation of rapid polymerase chain reaction-based detection of all length polymorphisms in the UGT 1A1 gene promoter. Diagn Mol Pathol. 2007; 16(1): 50-3.
21.
InnocentiF, UndeviaSD, IyerL, ChenPX, DasS, KocherginskyM, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004; 15; 22(8): 1382-8.
22.
IshiiT, MatsuseT, TeramotoS, MatsuiH, MiyaoM, HosoiT, et al. Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease. Thorax. 1999; 54(8): 693-6.
23.
KoshkinAA, SinghSK, NielsenP, RajwanshiVK, KumarR, MeldgaardM, et al. LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition. Tetrahedron. 1998; 54(14): 3607-3630.
24.
KruhGD. Introduction to resistance to anticancer agents. Oncogene. 2003; 22(47): 7262-4.
LiuJY, QuK, SferruzzaAD, BenderRA. Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals. Anticancer Drugs. 2007; 18(6): 693-6.
27.
MarcuelloE, AltésA, MenoyoA, Del RioE, Gómez-PardoM, BaigetM. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004; 91(4): 678-82.
28.
MattisonLK, SoongR, DiasioRB. Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics. Pharmacogenomics. 2002; 3(4): 485-92.
29.
MeinsmaR, Fernandez-SalgueroP, Van KuilenburgAB, Van GennipAH, GonzalezFJ. Human polymorphism in drug metabolism: Mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea. DNA Cell Biol. 1995; 14(1): 1-6.
30.
OfferSM, LeeAM, MattisonLK, FossumC, WegnerNJ, DiasioRB. A DPYD variant (Y186C) in individuals of african ancestry is associated with reduced DPD enzyme activity. Clin Pharmacol Ther. 2013; 94(1): 158-66.
31.
OfverholmA, ArkbladE, SkrticS, AlbertssonP, ShubbarE, EnerbäckC. Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene. Clin Biochem. 2010; 43(3): 331-4.
32.
PirulliD, GiordanoM, PuzzerD, CrovellaS, RigatoI, TiribelliC, et al. Rapid method for detection of extra (TA) in the promoter of the bilirubin-UDP-glucuronosyl transferase 1 gene associated with Gilbert syndrome. Clin Chem. 2000; 46(1): 129-31.
33.
RaidaM, SchwabeW, HäuslerP, Van KuilenburgAB, Van GennipAH, BehnkeD, et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin Cancer Res. 2001; 7(9): 2832-9.
34.
RandleRA, RaguzS, HigginsCF, YagüeE. Role of the highly structured 5'-end region of MDR1 mRNA in P-glycoprotein expression. Biochem J. 2007; 406(3): 445-55.
RubinaAY, Pan'kovSV, DementievaEI, Pen'kovDN, ButyginAV, VasiliskovVA, et al. Hydrogel drop microchips with immobilized DNA: properties and methods for large-scale production. Anal Biochem. 2004; 325(1): 92-106.
37.
RuzzoA, GrazianoF, LoupakisF, RulliE, CanestrariE, SantiniD, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 2007; 25(10): 1247-54.
38.
SakaedaT, NakamuraT, OkumuraK. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics. 2003; 4(4): 397-410.
39.
SchwabM, EichelbaumM, FrommMF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003; 43: 285-307.
40.
SkarkeC, GröschS, GeisslingerG, LötschJ. Single-step identification of all length polymorphisms in the UGT1A1 gene promoter. Int J Clin Pharmacol Ther. 2004; 42(3): 133-8.
41.
StoehlmacherJ, ParkDJ, ZhangW, YangD, GroshenS, ZahedyS, et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer. 2004; 91(2): 344-54.
42.
StrangeRC, SpiteriMA, RamachandranS, FryerAA. Glutathione-S-transferase family of enzymes. Mutat Res. 2001; 482(1-2): 21-6.
43.
StrassburgCP, KneipS, ToppJ, Obermayer-StraubP, BarutA, TukeyRH, et al. Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. J Biol Chem. 2000; 275(46): 36164-71.
44.
StrassburgCP, NguyenN, MannsMP, TukeyRH. Polymorphic expression of the UDP-glucuronosyltransferase UGT1A gene locus in human gastric epithelium. Mol Pharmacol. 1998; 54(4): 647-54.
45.
StrassburgCP. Pharmacogenetics of Gilbert's syndrome. Pharmacogenomics. 2008; 9(6): 703-15.
46.
SüzenHS, YüceN, GüvençG, DuyduY, ErkeT. TYMS and DPYD polymorphisms in a Turkish population. Eur J Clin Pharmacol. 2005; 61(12): 881-5.
47.
TakechiT, OkabeH, IkedaK, FujiokaA, NakagawaF, OhshimoH, et al. Correlations between antitumor activities of fluoropyrimidines and DPD activity in lung tumor xenografts. Oncol Rep. 2005; 14(1): 33-9.
48.
UzunkoyA, DilmecF, OzgonulA, van KuilenburgAB, AkkafaF. Investigation of IVS14+1G>A polymorphism of DPYD gene in a group of Turkish patients with colorectal cancer. Anticancer Res. 2007; 27(6B): 3899-902.
49.
van KuilenburgAB, MullerEW, HaasjesJ, MeinsmaR, ZoetekouwL, WaterhamHR, et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res. 2001; 7(5): 1149-53.
50.
Van KuilenburgAB, VrekenP, AbelingNG, BakkerHD, MeinsmaR, Van LentheH, et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet. 1999; 104(1): 1-9.
51.
VannemanM, DranoffG. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012; 12(4): 237-51.
52.
VrekenP, Van KuilenburgAB, MeinsmaR, SmitGP, BakkerHD, De AbreuRA, et al. A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis. 1996; 19(5): 645-54.
53.
WatanabeJ, MitaniY, KawaiY, KikuchiT, KogoY, Oguchi-KatayamaA, et al. Use of a competitive probe in assay design for genotyping of the UGT1A1*28 microsatellite polymorphism by the smart amplification process. Biotechniques. 2007; 43(4): 479-84.
54.
WatchkoJF, DaoodMJ, BiniwaleM. Understanding neonatal hyperbilirubinaemia in the era of genomics. Semin Neonatol. 2002; 7(2): 143-52.
55.
WatsonMA, StewartRK, SmithGB, MasseyTE, BellDA. Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis. 1998; 19(2): 275-80.
56.
WeiX, McLeodHL, McMurroughJ, GonzalezFJ, Fernandez-SalgueroP. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest. 1996; 98(3): 610-5.
57.
WildCP, YinF, TurnerPC, CheminI, ChapotB, MendyM, et al. Environmental and genetic determinants of aflatoxin-albumin adducts in the Gambia. Int J Cancer. 2000; 86(1): 1-7.
58.
WilkeRA, DolanME. Genetics and variable drug response. JAMA. 2011; 306(3): 306-7.
59.
ZhangBL, SunT, ZhangBN, ZhengS, LüN, XuBH, et al. Polymorphisms of GSTP1 is associated with differences of chemotherapy response and toxicity in breast cancer. Chin Med J (Engl). 2011; 124(2): 199-204.
